Substance P (Neurokinin 1) Receptor Antagonists Enhance Dorsal Raphe Neuronal Activity

Abstract

Substance P receptor [neurokinin 1 (NK1] antagonists (SPAs) represent a novel mechanistic approach to antidepressant therapy with comparable clinical efficacy to selective serotonin reuptake inhibitors (SSRIs). Because SSRIs are thought to exert their therapeutic effects by enhancing central serotonergic function, we have examined whether SPAs regulate neuronal activity in the dorsal raphe nucleus (DRN), the main source of serotonergic projections to the forebrain. Using in vivo electrophysiological techniques in the guinea pig, we found that administration of the highly selective NK1 receptor antagonist 1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-phenyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine (L-760735) caused an increase in DRN neuronal firing rate. However, unlike chronic treatment with fluoxetine, there was no detectable 5-HT1A autoreceptor desensitization. In vitro electrophysiological investigation showed that these effects were not mediated by a direct action in the DRN, an observation supported by immunocytochemical analysis that identified the lateral habenula (LHb) as a more likely site of action. Subsequently, we found that local application of L-760735 into the LHb increased firing in the DRN, which, together with our data showing that L-760735 increased metabolic activity in the cingulate cortex, amygdala, LHb, and DRN, indicates that the effects of L-760735 may be mediated by disinhibition of forebrain structures acting via a habenulo raphe projection. These findings support other evidence for an antidepressant profile of SPAs and suggest that regulation of DRN neuronal activity may contribute to their antidepressant mechanism of action but in a manner that is distinct from monoamine reuptake inhibitors.

Neurokinin1 Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization

“…In agreement with most studies of NK 1 antagonists Conley et al, 2002;Lejeune et al, 2002;Guiard et al, 2005;Gobbi et al, 2007), GR205171 did not affect the spontaneous activity of DRN-localized serotonergic neurones. However, its reduction of the inhibitory influence of citalopram and fluoxetine upon DRN firing mimics the effects of chronic administration of NK 1 antagonists (Haddjeri and Blier, 2001;Guiard et al, 2005), and of genetic elimination of NK 1 receptors in mice (Froger et al, 2001;Santarelli et al, 2001;Gobbi et al, 2007).…”

Ionic Mechanism of Long-Lasting Discharges of Action Potentials Triggered by Membrane Hyperpolarization in the Medial Lateral Habenula

“…In agreement with the anatomical circuitry, the electrical activity of the habenula has been shown to exert a powerful control over the activity of serotonin cells in the nucleus of dorsal raphe and dopamine cells in the ventral tegmental area and substantia nigra (Matsuda and Fujimura, 1992;Ferraro et al, 1996;Morris et al, 1999;Conley et al, 2002).…”

“…For instance, a change in habenular activity in response to either local electrical stimulation or a local injection of substance P antagonist resulted in alterations in the activity of serotonin cells in the dorsal raphe nucleus (Matsuda and Eaton, 1990;Ferraro et al, 1996;Conley et al, 2002). Because the projections to the dorsal raphe nucleus arise mainly from the medial part of the lateral habenula, and this habenular area receives its input mainly from the limbic regions of the forebrain Nauta, 1977, 1979), it is probable that the medial part of the lateral habenula signals the activity change in the limbic forebrain to the dorsal raphe nucleus for regulating serotonin cell activity.…”

Demonstration of the Efficacy and Safety of a Novel Substance P (NK1) Receptor Antagonist in Major Depression

“…Although the mechanism for this reduction is presently unclear, classical antidepressants do not block the NK 1 receptor (Kramer et al, 1998). Secondly, preclinical electrophysiological studies show that SPAs regulate serotonergic (Conley et al, 2002;Froger et al, 2001;Santarelli et al, 2001) and noradrenergic (Hahn and Bannon, 1999;Maubach et al, 2002) neuronal activity, but in a manner that is distinct from that seen with established monoamine reuptake inhibitors. Thirdly, data suggest that SPAs may produce additive or synergistic effects with established antidepressant drugs.…”